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Lutetium Lu 177 Dotatate

Class: Antineoplastic Agents
Chemical Name: 2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium-177(3+)
Molecular Formula: C65H87LuN14O19S2
Brands: Lutathera

Introduction

Lutetium Lu 177 dotatate is an antineoplastic agent.1

Uses for Lutetium Lu 177 Dotatate

Lutetium Lu 177 dotatate has the following uses:

Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.1

Lutetium Lu 177 Dotatate Dosage and Administration

General

Lutetium Lu 177 dotatate is available in the following dosage form(s) and strength(s):

Injection: 370 MBq/mL (10 mCi/mL) in single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage & Administration Section
  • Verify pregnancy status in females of reproductive potential prior to initiating lutetium Lu 177 dotatate.1

  • Administer 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.1

  • Administer long-acting octreotide 30 mg intramuscularly 4 to 24 hours after each lutetium Lu 177 dotatate dose and short-acting octreotide for symptomatic management.1

  • Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing lutetium Lu 177 dotatate until disease progression or for up to 18 months following treatment initiation.1

  • Premedicate with antiemetics 30 minutes before recommended amino acid solution.1

  • Initiate recommended intravenous amino acid solution containing L-lysine and L-arginine 30 minutes before lutetium Lu 177 dotatate infusion; continue during and for 3 hours after lutetium Lu 177 dotatate infusion. Do not reduce dose of amino acid solution if lutetium Lu 177 dotatate dose is reduced.1

  • Modify lutetium Lu 177 dotatate dose based on adverse reactions.1

  • Prepare and administer as recommended.1

Cautions for Lutetium Lu 177 Dotatate

Contraindications

None.1

Warnings/Precautions

Risk From Radiation Exposure

Lutetium Lu 177 dotatate contributes to a patient’s overall long-term radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer.1

Radiation can be detected in the urine for up to 30 days following lutetium Lu 177 dotatate administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with lutetium Lu 177 dotatate consistent with institutional good radiation safety practices and patient management procedures. 1

Myelosuppression

In NETTER-1, myelosuppression occurred more frequently in patients receiving lutetium Lu 177 dotatate with long-acting octreotide compared to patients receiving high-dose long-acting octreotide (all grades/grade 3 or 4): anemia (81%/0) versus (54%/1%); thrombocytopenia (53%/1%) versus (17%/0); and neutropenia (26%/3%) versus (11%/0). In NETTER-1, platelet nadir occurred at a median of 5.1 weeks following the first dose. Of the 59 patients who developed thrombocytopenia, 68% had platelet recovery to baseline or normal levels. The median time to platelet recovery was 2 months. Fifteen of the nineteen patients in whom platelet recovery was not documented had post-nadir platelet counts. Among these 15 patients, 5 improved to Grade 1, 9 to Grade 2, and 1 to Grade 3.1

Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.1

Secondary Myelodysplastic Syndrome and Leukemia

In NETTER-1, with a median follow-up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving lutetium Lu 177 dotatate with long-acting octreotide compared to no patients receiving high-dose long-acting octreotide. In ERASMUS, 15 patients (1.8%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to the development of MDS was 28 months (9 to 41 months) for MDS and 55 months (32 to 155 months) for acute leukemia.1

Renal Toxicity

In ERASMUS, 8 patients (<1%) developed renal failure 3 to 36 months following lutetium Lu 177 dotatate. Two of these patients had underlying renal impairment or risk factors for renal failure (e.g., diabetes or hypertension) and required dialysis.1

Administer the recommended amino acid solution before, during and after lutetium Lu 177 dotatate to decrease reabsorption of lutetium Lu 177 dotatate through the proximal tubules and decrease the radiation dose to the kidneys. Do not decrease the dose of the amino acid solution if the dose of lutetium Lu 177 dotatate is reduced. Advise patients to urinate frequently during and after administration of lutetium Lu 177 dotatate. Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue lutetium Lu 177 dotatate based on severity of reaction.1

Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. Lutetium Lu 177 dotatate has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min).1

Hepatotoxicity

In ERASMUS, 2 patients (<1%) were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure.1

Monitor transaminases, bilirubin and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue lutetium Lu 177 dotatate based on severity of reaction.1

Neuroendocrine Hormonal Crisis

Neuroendocrine hormonal crises, manifesting with flushing, diarrhea, bronchospasm and hypotension, occurred in 1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial lutetium Lu 177 dotatate dose. Two (<1%) patients were reported to have hypercalcemia.1

Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.1

Embryo-fetal Toxicity

Based on its mechanism of action, lutetium Lu 177 dotatate can cause fetal harm. There are no available data on the use of lutetium Lu 177 dotatate in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including lutetium Lu 177 dotatate, have the potential to cause fetal harm. 1

Verify pregnancy status of females of reproductive potential prior to initiating lutetium Lu 177 dotatate.1

Advise females and males of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with lutetium Lu 177 dotatate and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose.1

Risk Of Infertility

Lutetium Lu 177 dotatate may cause infertility in males and females. The recommended cumulative dose of 29.6 GBq of lutetium Lu 177 dotatate results in a radiation absorbed dose to the testis and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy.1

Specific Populations

Pregnancy

Risk Summary: Based on its mechanism of action, lutetium Lu 177 dotatate can cause fetal harm. There are no available data on lutetium Lu 177 dotatate use in pregnant women. No animal studies using lutetium Lu 177 dotatate have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including lutetium Lu 177 dotatate, have the potential to cause fetal harm. Advise pregnant women of the risk to a fetus.1

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Lactation

There are no data on the presence of lutetium Lu 177 dotatate in human milk, or its effects on the breastfed infant or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with lutetium Lu 177 dotatate and for 2.5 months after the final dose.1

Females and Males of Reproductive Potential

Verify pregnancy status of females of reproductive potential prior to initiating lutetium Lu 177 dotatate.1

Lutetium Lu 177 dotatate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the final dose of lutetium Lu 177 dotatate.1

Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of lutetium Lu 177 dotatate.1

The recommended cumulative dose of 29.6 GBq of lutetium Lu 177 dotatate results in a radiation absorbed dose to the testis and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy.1

Pediatric Use

The safety and effectiveness of lutetium Lu 177 dotatate have not been established in pediatric patients.1

Geriatric Use

Of the 1325 patients treated with lutetium Lu 177 dotatate in clinical trials, 438 patients (33%) were 65 years and older. The response rate and number of patients with a serious adverse event were similar to that of younger subjects.1

Renal Impairment

No dose adjustment is recommended for patients with mild to moderate renal impairment; however, patients with mild or moderate renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild to moderate impairment. The safety of lutetium Lu 177 dotatate in patients with severe renal impairment (creatinine clearance <30 mL/min by Cockcroft-Gault) or end-stage renal disease has not been studied.1

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment. The safety of lutetium Lu 177 dotatate in patients with severe hepatic impairment (total bilirubin >3 times upper limit of normal and any AST) has not been studied.1

Common Adverse Effects

Adverse Reactions Section

Most common Grade 3–4 adverse reactions (≥4% with a higher incidence in lutetium Lu 177 dotatate arm) are lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Somatostatin Analogs: Discontinue long-acting analogs for at least 4 weeks and short-acting octreotide at least 24 hours prior to each lutetium Lu 177 dotatate dose.1

Actions

Mechanism of Action

Lutetium Lu 177 dotatate binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors, the compound is internalized. The beta emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells.1

Advice to Patients

Advise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures.1

Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, or increased bleeding or bruising.1

Advise patients of the potential for secondary cancers, including myelodysplastic syndrome and acute leukemia.1

Advise patients to hydrate and urinate frequently during and after administration of lutetium Lu 177 dotatate.1

Advise patients of the need for periodic laboratory tests to monitor for hepatotoxicity.1

Advise patients to contact their health care provider for signs or symptoms that may occur following tumor-hormone release, including severe flushing, diarrhea, bronchospasm, and hypotension.1

Advise pregnant women and males and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.1

Advise females of reproductive potential to use effective contraception during treatment with lutetium Lu 177 dotatate and for 7 months after the final dose.1

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with lutetium Lu 177 dotatate and for 4 months after the final dose.1

Advise females not to breastfeed during treatment with lutetium Lu 177 dotatate and for 2.5 months after the final dose.1

Advise female and male patients that lutetium Lu 177 dotatate may impair fertility.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Lutetium Lu 177 Dotatate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

10 mCi/1 mL

Lutathera

Advanced Accelerator Applications USA Inc

AHFS Drug Information. © Copyright 2018, Selected Revisions February 19, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Advanced Accelerator Applications USA, Inc. Lutathera (Lutetium Lu 177 dotatate) injection prescribing information. 2018 Jan.

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